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(Stroke. 2002;33:578.)
© 2002 American Heart Association, Inc.

Original Contributions

Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke

John R. Toomey, PhD; Richard E. Valocik, BS; Paul F. Koster, BS; Melanie A. Gabriel, MA; Matt McVey, BS; Timothy K. Hart, PhD; Eliot H. Ohlstein, PhD; Andrew A. Parsons, PhD Frank C. Barone, PhD

From the Departments of Cardiovascular Pharmacology (J.R.T., R.E.V., P.F.K., M.A.G., M.M., E.H.O., F.C.B.), Neurology (A.A.P.), and Safety Assessment (T.K.H.), GlaxoSmithKline, King of Prussia, Pa.

Correspondence to John R. Toomey, PhD, Cardiovascular Pharmacology, GlaxoSmithKline, 709 Swedeland Rd, PO Box 1539, Mail Code UW2510, King of Prussia, PA 19406. E-mail John_R_Toomey{at}gsk.com

Background and Purpose— Although used clinically to prevent stroke, there are few examples of anticoagulant investigations in the treatment of acute thromboembolic stroke in animal models. The treatment of thromboembolic stroke in experimental models has been investigated almost exclusively around the use of tissue plasminogen activator (tPA). In this study, using a rat thromboembolic stroke model, we investigated the use of an inhibitory anti–factor IX(a) monoclonal antibody (SB 249417) for the treatment of thromboembolic stroke and compared its efficacy to that of tPA.

Methods— Stroke was initiated by delivering 6 clots into the internal carotid artery. After 2, 4, or 6 hours, rats received either intravenous vehicle, 10.0 mg/kg tPA, or 1.0, 2.0, or 3.0 mg/kg SB 249417. At 24 hours after stroke, infarct volumes and neurological deficits were assessed.

Results— Treatment with tPA 2, 4, or 6 hours after stroke reduced infarct volumes by 35% (P=NS), 45%, and 39%, respectively. tPA treatment did not improve neurological deficits at any time point. Treatment with SB 249417 (3.0 mg/kg) 2, 4, or 6 hours after stroke reduced infarct volumes by 44%, 50%, and 13% (P=NS), respectively. Neurological deficits were reduced by 49%, 42%, and 13% (P=NS), respectively. Neither mortality nor hemorrhage was affected by either treatment.

Conclusions— The data indicate that the inhibition of factor IX(a) within 4 hours of thromboembolic stroke produced a more favorable outcome than tPA. When treatment was initiated 6 hours after stroke, the benefits of factor IX(a) inhibition were lost, whereas tPA continued to suppress lesion development, albeit without a corresponding improvement in functional deficits. This study suggests that cerebral ischemia and the resultant perfusion deficit are exacerbated by the activation of blood coagulation and that anticoagulants like SB 249417 may find utility in the treatment of ischemic stroke.

Key Words: anticoagulants • factor IX • ischemia • thromboembolism • tissue plasminogen activator • rats

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